Formation and resolution of ibuprofen lysinate

ABSTRACT

A process is disclosed for the formation and resolution of (S)-ibuprofen-(S)-lysine. The process employs preferential crystallization to separate a pair of diasteromeric salts, (S)-ibuprofen-(S)-lysine and (R)-ibuprofen-(S)-lysine.

BACKGROUND OF THE INVENTION

Pharmacological properties are often dependent on a particularstereochemistry and thus the resolution of a racemic mixture is a usefulchemical process.

Ibuprofen, a well know analgesic, is a racemic mixture of carboxylicacids of formula (I): ##STR1## However, although ibuprofen is marketedas the racemic mixture, the (S)-enantiomer is known to be the activeagent. If (S)-ibuprofen is to be sold commercially there exists a needfor an efficient preferential resolution of racemic ibuprofen.Furthermore it would be desirable for the resolution process to leaddirectly to an amino acid salt of (S)-ibuprofen since such salts aremore soluble and thus may offer pharmaceutical advantages over thecarboxylic acid.

There are two classical routes to the resolution of racemic mixturessuch as (R)(S)-ibuprofen.

The first requires finding a chiral amine which, when reacted with the(R)(S)-ibuprofen, will form diastereomeric salts the solubilities ofwhich are so different from each other that the diastereomers may beseparated, one from the other, by simple crystallization.

The above procedure has two disadvantages: chiral amines, such as(S)-alpha-methylbenzylamine, are expensive reagents, and the product ofthe separation is not (S)-ibuprofen, but its amine salt. Thus theseparation process must be supplemented with procedures to free the(S)-ibuprofen from its amine salt, recover the chiral amine, and, ifdesired, convert the (S)-ibuprofen to a preferred salt such as an aminoacid salt.

The second classical resolution route is preferential crystallization.However, (R)(S)-ibuprofen as such cannot be resolved by preferentialcrystallization, or any other crystallization technique, because as acrystalline material it takes the form of a racemic compound rather thana mixture of crystals of (R)-ibuprofen and crystals of (S)-ibuprofen.Thus, to use preferential crystallization requires finding a derivativeof ibuprofen which does not crystallize in the form of a racemiccompound. Non-chiral amines, such as tert-butylamine and diethylamineare suitable for this purpose. However, except for amine costs,preferential crystallization via these amine salts shares thedisadvantages cited for the chiral amine route described above.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is a process for the formation and resolution of(S)-ibuprofen-(S)-lysine, which comprises:

(a) contacting (R)(S)-ibuprofen and (S)-lysine in an aqueous-organicsolvent mixture;

(b) separating any suspended solid from the mixture;

(c) cooling the clear mixture until the mixture is supersaturated withrespect to each of the (S)-ibuprofen-(S)-lysine and(R)-ibuprofen-(S)-lysine salts;

(d) contacting the supersaturated mixture with a slurry of(S)-ibuprofen-(S)-lysine in an aqueous-organic solvent;

(e) separating the formed crystalline (S)-ibuprofen-(S)-lysine.

Racemic ibuprofen is mixed with an organic solvent which is misciblewith water. Illustrating such solvents are ethanol, methanol,isopropanol and acetone. The (S)-lysine is mixed with water, and theibuprofen and lysine solutions are combined.

The mixture is agitated for a time period sufficient to crystallize allthe salts, if any, in excess of the solubility limit. The suspendedsalts are separated to obtain a clear mother liquor which is generallysaturated with respect to the diastereomeric salts(S)-ibuprofen-(S)-lysine and (R)-ibuprofen-(S)-lysine. Filtration may beemployed to effect the separation. The liquor is then cooled to atemperature at which it is supersaturated with respect to each of thediastereomeric salts. It is preferred that the liquor be cooled to thepoint at which maximum supersaturation is obtained with respect to eachsalt without nucleation of either crystallizable species. Typically thetemperature of the mother liquor must be lowered by about 5° C. to reachmaximum supersaturation without precipitation of either salt. However,the degree of cooling will depend on the particular solvent composition.The supersaturated liquor is then passed into a vessel containing aslurry of (S)-ibuprofen-(S)-lysine, hereafter referred to as the(S,S)-salt, in the same solvent system employed above for the mixture ofracemic ibuprofen and (S)-lysine. In the presence of the (S,S) saltcrystals acting as a seed, the supersaturation of the (S,S)-salt in thefeed liquor is released by the growth of further crystals of the(S,S)-salt. Conversely there is little or no change in the(R)-ibuprofen-(S)-lysine (hereafter referred to as the (R,S)-salt)supersaturation because the growth rate of the (R,S) crystals isessentially zero in the absence of any initial (R,S) salt seed. The(S,S) crystals are then separated and washed with aqueous-organicsolvent to yield (S)-ibuprofen-(S)-lysine of purity≧98%. Separation maybe accomplished by filtration or centrifugation.

The above described process can be employed on a batch or a continuousbasis. In the continuous procedure the mother liquor obtained after theseparation of (S,S) crystals is placed back into step (a) to reform amixture of the diastereomeric salts.

The above process is an implementation of the principle of preferentialcrystallization a process which takes advantage of the fact that thegrowth rate of crystals is a function not only of the solutionsupersaturation, which provides the driving force for crystal growth,but also of the amount of seed crystal surface available for growth. Byproviding a large amount of (S,S) salt seed crystal surface, andessentially no (R,S) salt seed crystal surface, an environment iscreated in which (S,S) salt crystals grow at a substantial rate, and(R,S) salt crystals at a negligible rate. The practical application ofpreferential crystallization was possible in the present invention dueto Applicants' surprising findings that ibuprofen lysine can tolerate ahigh degree of supersaturation in solution without crystal growth andthat (S)-ibuprofen-(S)-lysine and (R)-ibuprofen-(S)-lysine form amixture and not a compound.

The present process can be successfully accomplished over a range oftemperatures at the salt formation step (a) and the supersaturation step(c). The only restriction is that the temperature in step (c) not causespontaneous nucleation of either crystallizable species. Typically, saltformation in Step (a) is accomplished at about 30° C. and withethanol/H₂ O (97/3 v/v) as the solvent mixture and supersaturation isachieved with about a 5° C. cooling, to about 25° C.

The present invention can be operated across a range of organic solventto water ratios. Higher water concentrations increase the solubilitiesof the two salts. With ethanol/water mixtures, water concentrationsabove 5% V/V lead to the crystallization of the (S,S) salt in the formof its monohydrate; the anhydrous form is obtained from lower waterconcentration. Preferably the percentage water by volume is less than15%. Illustrative ratios of ethanol/water are 97/3 and 92/8 v/v.

Although the above description cites only (S)-lysine as the salt formingagent for the resolution, (R)-lysine could be used with similar effect.In this case (R)-ibuprofen-(R)-lysine would be employed in the seedingstage and high purity crystalline (R)-ibuprofen-(R)-lysine would beobtained.

Racemic ibuprofen and (S)-lysine and (R)-lysine are all commerciallyavailable.

The following example illustrates the process of the present inventionand as such is not to be considered as limiting the invention set forthin the claims appended hereto:

EXAMPLE 1 Preparation and Resolution of (S)-Ibuprofen-(S)-Lysine

167 grams of racemic ibuprofen and 118 grams of (S)-lysine were chargedinto 180 cc of water and 5.82 liters of ethanol were added. Theresulting slurry was agitated and aged at 30° C. for 24 hours. A clearliquor was drawn off through a filter and the liquor cooled to 25° C.The resulting supersaturated liquor was then added to a slurry of 50grams of 99.4% (S)-ibuprofen-(S)-lysine. The precipitated solid wasseparated by filtration and the mother liquor recycled to the slurrymixture of racemic ibuprofen and (S)-lysine. The procedure was continueduntil essentially all the (S)-ibuprofen in the original charge wasdepleted. This procedure resulted in the formation of 144 grams of98.1-98.8% pure (S)-ibuprofen-(S)-lysine.

EXAMPLE 2 Preparation and Resolution of (S)-Ibuprofen-(S)-Lysine

1. 2.0 kg racemic ibuprofen and 1.6 kg S-lysine monohydrate werecombined with 18 to 20 liters of EtOH/Water 97/3 V/V solvent mixture.The solution was charged to a feed tank which contained about 20 to 30gallons seed bed of (R)-ibuprofen-(S)-lysine and(S)-ibuprofen-(S)-lysine with a slurry concentration of about 150 liter.

2. A slurry of about 10 liters was transferred from the feed tank to anempty dissolver.

3. The dissolver temperature was adjusted to about 31° C.

4. The slurry in the dissolver was filtered and the filtrate sent to thecrystallizer at a rate of 600 ml/min. and the retentate returned to thedissolver.

5. The crystallizer contained about 30 liter seed bed of(S)-ibuprofen-(S)-lysine with a slurry concentration of about 150gram/liter and a crystallizer temperature of about 23° C.

6. The slurry in the crystallizer was filtered and the filtrate sentback to the dissolver at a rate such that the liquid level in thecrystallizer remained constant while the retentate was returned to thecrystallizer.

7. After about 6 to 7 hours continuous operation of steps 3 to 6, allthe (S)-ibuprofen-(S)-lysine in the dissolver was depleted. About 4liters crystallizer slurry was harvested and filtered. The cakecontained about 600 grams (S)-ibuprofen-(S)-lysine with an opticalpurity of about 99%.

8. 4 liters of dissolver filtrate was sent to the crystallizer tomaintain the liquid level in the crystallizer.

9. About 6 liters of dissolver slurry which contained mainly the(R)-ibuprofen-(S)-lysine was transferred to a container.

12. Steps 2 to 9 were repeated.

What is claimed is:
 1. A process for the formation and resolution of(S)-ibuprofen-(S)-lysine which comprises:(a) contacting (R)(S)-ibuprofenand (S)-lysine in an aqueous-organic solvent mixture; (b) separating anysuspended solid from the mixture; (c) cooling the clear mixture untilthe mixture is supersaturated with respect to each of the (S,S) and(R,S) salts; (d) contacting the supersaturated mixture with a slurry of(S)-ibuprofen-(S)-lysine in an aqueous-organic solvent; (e) separatingthe formed crystalline (S)-ibuprofen-(S)-lysine.
 2. A process of claim 1wherein the aqueous-organic solvent is selected from the groupconsisting of: water/ethanol, water/methanol, water/isopropanol, andwater/acetone.
 3. A process of claim 2 wherein the aqueous/organicsolvent is water/ethanol.
 4. A process of claim 3 wherein the volumepercent of water is less than 15 percent.
 5. A process of claim 4wherein the volume percent of water is 8 percent or less.
 6. A processof claim 5 wherein the volume percent of water is 3 percent or less. 7.A process of claim 6 wherein the Step (c) cooling is about 5° C.
 8. Aprocess for the resolution of (S)-ibuprofen-(S)-lysine whichcomprises:(i) contacting a mixture supersaturated in(S)-ibuprofen-(S)-lysine and (R)-ibuprofen-(S)-lysine in anaqueous-organic solvent with a slurry of (S)-ibuprofen-(S)-lysine in anaqueous-organic solvent; (ii) separating the formed crystalline(S)-ibuprofen-(S)-lysine.